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  • EPV105/#237 Combination targeted treatment with mek and pan-ERBB inhibitors enhances antitumor activity in erbb amplified ex-vivo serous endometrial cancer cells

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EPV105/#237 Combination targeted treatment with mek and pan-ERBB inhibitors enhances antitumor activity in erbb amplified ex-vivo serous endometrial cancer cells
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  1. A Larish1,
  2. W-H Lin2,
  3. J Smadbeck3,
  4. S Sotiriou3,
  5. J Cheville3,
  6. F Harris1,
  7. R Feathers1,
  8. J Lynch1,
  9. A Kumar4,
  10. M Block5,
  11. L Jones1,
  12. G Karagouga1,
  13. A Mccune1,
  14. A Mansfield5,
  15. S Murphy3,
  16. A Mariani4,
  17. G Vasmatzis3,
  18. P Anastasiadis2 and
  19. J Weroha5
  1. 1Mayo Clinic, Obstetrics and Gynecology, Rochester, USA
  2. 2Mayo Clinic, Department of Laboratory Medicine and Pathology, Jacksonville, USA
  3. 3Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, USA
  4. 4Mayo Clinic, Division of Gynaecologic Surgery, Department of Obstetrics and Gynaecology, Rochester, USA
  5. 5Mayo Clinic, Medical Oncology, Rochester, USA

Abstract

Objectives ERBB pathway alterations present therapeutic targets in high grade endometrial cancer (EC), but efficacy can be limited by persistent co-activation of other ERBB binding partners. The efficacy of dual-inhibition MEK+pan-ERBB or BET+pan-ERBB in an ERBB2/ERBB3 amplified EC was investigated via 3D microcancer ex-vivo cell assay.

Methods Tumor was prospectively collected from a patient with stage IIIc1 serous EC. Whole exome, mRNA, and MatePair genomic characterization was performed. Tumor cells were grown in 3D culture and subjected to titrating drug treatments. Cell viability was determined by the CellTiter-Glo Luminescent Assay. Data transformation and dose-response curves were generated using GraphPad PRISM using the variable slope model. CalcuSyn software with the Chou-Talalay method analyzed drug interactions and synergy. Afatinib, binimetanib, and JQ1 were used to inhibit pan-ERBB, MEK1/2, BET, respectively. For translational relevance, inhibitory effect was defined as percent reduction in ATP from baseline at the physiologically achievable concentration (maximum plasma concentration (Cmax) value).

Results Sequencing revealed amplifications of ERBB2 (17q12), RAF1, c-myc, and ERBB3 (12q13.2) low-level gain. Inhibition of viability was moderate by single agents: Afatinib, binimetanib, JQ1, as shown by inhibitory effect values of 14.4%,47.8%, 8.8%, respectively at physiologically achievable concentrations (Cmax) of afatinib. Combinations demonstrated increasing inhibitory effect values: 99.7% for Afatinib+ binimetanib, and 99.5% for Afatinib+JQ1. Synergy was evidenced for both combinations by a combination index <1 (figure 1).

Abstract EPV105/#237 Figure 1
Abstract EPV105/#237 Figure 1

Microcancer ex vivo exposure to MEK+pan-ERBB inhibitors. Dose response curves of single and combination treatments (left) were 10-fold titrated across 8 log doses for each agent. The highest concentration (i.e. fraction of ful (FoF)=1) of afatnib, binimetinib and afatinib+JQ1 was 3 uM, 10 uM, and 50 uM, respectively. The physiologically achieavable concentration of afatinib is insicated (dotted lines). A comnination index (CI, right) was used to assess synergy with afatinib+binimtinib and afatinib+JQ1 as shown by Fa-CI plots.

Conclusions Combined inhibition of pan-ERBB with inhibition of MEK or BET proteins synergistically suppress viability in patient-derived serous EC harboring ERBB amplifications.

http://dx.doi.org/10.1136/ijgc-2021-IGCS.175

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